Impact of BA.1, BA.2, and BA.4/BA.5 Omicron mutations on therapeutic monoclonal antibodies.

The emergence of Omicron SARS-CoV-2 subvariants (BA.1, BA.2, BA.4, and BA.5), with an unprecedented number of mutations in their receptor-binding domain (RBD) of the spike-protein, has fueled a resurgence of COVID-19 infections, posing a major challenge to the efficacy of existing vaccines and monoclonal antibody (mAb) therapeutics. We conducted a systematic molecular dynamics (MD) simulation to investigate how the RBD mutations of these subvariants affect the interactions with broad mAbs including AstraZeneca (COV2-2196 and COV2-2130), Brii Biosciences (BRII-196), Celltrion (CT-P59), Eli Lilly (LY-CoV555 and LY-CoV016), Regeneron (REGN10933 and REGN10987), Vir Biotechnology (S309), and S2X259. Our results show a complete loss of binding for COV2-2196, BRII-196, CT-P59, and LY-CoV555 with all Omicron RBDs. Additionally, REGN10987 totally loses its binding with BA.1, but retains a partial binding with BA.2 and BA.4/5. The binding reduction is significant for LY-CoV016 and REGN10933 but moderate for COV2-2130. S309 and S2X259 retain their binding with BA.1 but exhibit decreased binding with other subvariants. We introduce a mutational escape map for each mAb to identify the key RBD sites and the corresponding critical mutations. Overall, our findings suggest that the majority of therapeutic mAbs have diminished or missing activity against Omicron subvariants, indicating the urgent need for a new therapeutic mAb with a better design.